Breast cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in women. While endocrine therapies have proven to be initially effective, almost half of breast cancer patients eventually present recurrent tumors that are resistant to these therapies. The reasons behind endocrine therapy resistance remain poorly understood, and as a consequence there are no prognostic markers or therapeutic alternatives with which to treat these patients.
Estrogen receptor alpha (ERα) is involved in the pathogenesis of over 70% of all breast cancers, and plays a role as both a therapeutic target and prognostic factor (Sorlie, T. et al. 2001. Proc. Natl. Acad. Sci. USA 98:10869-10874). The receptor stimulates cell proliferation by binding DNA at regulatory elements in response to a diverse number of stimuli such as estrogens and growth factors (Carroll, J. S. et al. 2005. Cell 122:33-43). Currently, the main therapeutic strategies for treatment of breast cancer consist of modulating ERα activity by antagonizing its endogenous ligand (i.e., estrogen) with a selective estrogen receptor modulator (SERM) such as tamoxifen, or by inhibiting aromatase-driven estrogen synthesis (aromatase inhibitor). Unfortunately, all patients with ERα-positive metastatic breast cancer and half or more of ERα-positive early stage breast cancers will develop resistance to endocrine therapy (Swanton, C. and J. Downward. 2008. Cancer Cell 13:83-85).
Growing evidence suggests that growth factor pathways, which activate ERα independently from estrogen, may be involved in the development of drug resistance in breast cancer. HER2, an epidermal growth factor family receptor, has clearly been linked to the development of endocrine therapy resistance in breast cancer (Shou, J. et al. 2004. J. Natl. Cancer Inst. 96:926-935). Recent studies support a role for the epidermal growth factor receptor (EGFR) in breast cancer (Johnston, S. R. 2010. Clin. Cancer Res. 16:1979-1987). Epidermal growth factor (EGF) has been shown to induces a distinct ERα genome-wide DNA binding profile (known as its cistrome) compared to estrogen in breast cancer cells (Lupien, M. et al. 2010. Genes Dev. 24:2219-2227). More importantly, while the estrogen-ERαcistrome is associated with genes of the ERα-positive, or projected good prognosis signature of breast cancer, the EGF-ERα cistrome defines a subset of genes associated with HER2 and poor prognosis signature (Lupien, M. et al. 2010. Genes Dev. 24:2219-2227). Furthermore, EGF-ERα mediated tumor cell growth is not responsive to tamoxifen treatment (Lupien, M. et al. 2010. Genes Dev. 24:2219-2227). These data suggest that EGF-induced ERα activation is central in the development of endocrine therapy resistance in ERα-positive breast cancers. Unfortunately, there are no predictive markers for response to endocrine therapy in ERα-positive breast cancers.
U.S. Patent Application Nos. 2008/0207714, 2009/0222387, and 2009/0239223) disclose methods for diagnosing or treating breast cancer (2008/0207714 and 2009/0222387), or a method for predicting breast cancer response to taxane-based chemotherapy (2009/0239223). PBX1 is listed in these patents as one of a group of genes that might be involved in carcinogenesis, yet none of the applications disclose use of PBX1 as a novel marker for breast cancer or drug treatment of breast cancer.
Svingen and Tonissen (2003. Cancer Biol. Ther. 2:518-523) teach that human HOX genes are expressed in breast cancer cells in vitro, and included measurement of the HOX co-factor PBX1. Although HOX genes were shown to be specifically dysregulated in malignant breast cancer cells, the co-factor PBX1 was not dysregulated. The authors concluded that HOX genes, but not the co-factor PBX1, commit cancer cells to re-differentiate and undergo oncogenic transformation.
Fernandez et al. (2008. Cancer Lett. 266:144-155) disclose that PBX1 plays a role in HoxB7 oncogenic activity in breast cancer cells in vitro. The authors show that in SkBr3/B7 cells, a type of breast cancer cell, HoxB7 is important in the tumorigenic process.
Xiao et al. (2010. Oncogene Epub September 13) disclose that the Notch3 gene is activated in a model of inflammatory breast carcinoma. Upregulation of Notch3 was shown to lead to increased expression of several downstream targets including PBX1.